The importance of interactions between the fragment of crystallization (Fc) region of various IgG isoforms and the array of Fc?Rs expressed by effector immune cells in establishment of broad immunity to influenza viruses is increasingly recognized. However, the translational value of studies of these pathways in mice is limited in part by major species differences in the number, structure and expression pattern of the Fc?Rs, particularly the low affinity receptors clustered on chromosome 1. Similarly, although both the mouse and the human IgG locus encode four IgG constant region genes and thus produce four IgG isotypes, divergence between the species has made it difficult to assign mouse orthologs to human IgG constant region genes. These species differences have also limited the use of the mouse as a preclinical tool for evaluating reagents such as vaccines and humanized monoclonal antibodies (mAbs).To address this, we have generated mice in which the three loci encoding mouse IgG receptors, Fc?RII/III/IV, Fc?R1a, and FcRn (the IgG transporter), are humanized by syntenic replacement. Mice humanized for the FC?Rs and derived lines expressing only one of the three low affinity FCGR activating receptor genes, FCGR2A, FCGR2C or FCGR3A, will be used to evaluate the role of these receptors in antibody-mediated protection against influenza. The contribution of human Fc receptors would ideally be studied in animals in which the IgG isotypes produced in response to virus have human Fc regions, ensuring that the Fc-FC?R interactions mimic those observed in humans. We address this limitation by humanization of the ~200 kb mouse IgH constant region, as well as the constant region for the kappa light chains. As embryonic stem cells from mice humanized for the FCGR genes are used for this genome engineering, the mice generated will not only produce human IgG isoforms, but these isoforms will interact with human effector FC?Rs on effector cell populations.These animals will provide a model for evaluation of the effectiveness of human mAbs as well as for defining Fc-Fc?R pathways whose engagement modulates the pathogenesis of disease after viral exposure and/or improves immunity in vaccinated animals.